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Does Cell Growth Predict Protein Productivity?
Viable cell density (VCD) is defined as the number of cells that are alive in a given volume of
media. VCD is a measurement commonly taken during upstream process development. Several
different methods are available to scientists to use as screening tool while optimizing a media
strategy for a particular CHO cell line. One popular screening tool is to track the VCD of different
conditions to determine proliferation rates and viability of the cells for the length of the run.
Ultimately, a combination of measurements, for example VCD and protein titer, would be
analyzed to determine which media strategy would be chosen for the clone. How do
proliferation rate and VCD relate to protein titer, if at all? In this edition of Did You Know, we
examine the relationship between cell growth and protein productivity with the help of a study
evaluating cell metabolism in fed-batch CHO cell culture.
To Grow or Produce? Different Cell Metabolism is Required for Different Functions
A typical growth curve for cells in a production run begins with early exponential growth and is
followed by late exponential growth, stationary phase, and decline (cell death). In a study
performed by a group at Amgen, antibody production and cell metabolism were evaluated at
each fed-batch phase. Antibody production was found to be at its minimum during early
exponential phase and at its highest during stationary phase. As nutrient availability and cell
density changed over the course of the production run, cell metabolism also changed. For
example, cells took in the most glutamine and produced the most lactate in early exponential
phase, while they took in other amino acids and produced the most carbon dioxide during
stationary phase. Their findings confirmed that cell growth and protein production are not
correlated and have very different nutrient uptake and metabolism (1).
What do these findings say about the relationship between VCD and protein productivity? The
study shows the relationship between declining biomass (or less total cell density) and an
increase in monoclonal antibody. The late stage of the cell lifecycle is when the CHO cell is a
highly productive protein factory. Associated with those different stages of the life cycle are
different resource needs observed over the bioproduction run. In effect, active proliferation and
increasing cell density is counter to protein productivity. Therefore, fast proliferation and
increased VCD may not correlate with an increased yield. For example, a shake flask with high
protein productivity per cell may lead to the highest overall protein titer, even if it has less total
cells than the control shake flask. In this case, the VCD may not correlate with protein titer.
Of course, there are situations where VCD and protein titer do correlate. As an example, a
correlation might be observed when a cell population is growing quickly and producing protein,
leading to a high cell count and high overall protein titer. However, a high number of cells
producing protein is not always desirable, as there may be issues downstream with purification
when starting with a high biomass.
Conclusions and Solutions
When the goal is to increase protein titer, VCD is a valuable metric to gauge the proliferative
capacity of the cell, but it is not the only indicator of protein yield. Experimental conditions (such
as media or feeds) that increase per cell productivity may have equal or lower VCD than the
control, while still increasing overall protein titer.
Cell-Ess universal protein titer boost and enhancer can be used as a supplement or feed to
improve efficiency by increasing protein productivity. In recent studies, Cell-Ess used as an initial
supplement at 1% (v/v) in a serum-free system increased monoclonal antibody in raw titer by
25% and on a per cell basis by 40%. By increasing protein productivity without increasing
biomass, Cell-Ess may help reduce issues downstream during purification.
Contact us and learn more about Cell-Ess and the benefits it provides to the bioprocessing
industry by email [email protected] or phone 1-844-Ess-Prod (377-7763).
References
1Templeton N,
Dean J, Reddy P, Young JD. Peak Antibody Production is Associated With
Increased Oxidative Metabolism in an Industrially Relevant Fed-Batch CHO Cell Culture.
Biotechnol Bioeng. 2013. 110(7): 2013-2024.